The therapeutic effect of artesunate on rosacea through the inhibition of the JAK/STAT signaling pathway

Retraction in: /10.3892/mmr.2023.13127

  • Authors:
    • Ting Li
    • Qingwen Zeng
    • Xingming Chen
    • Guojiang Wang
    • Haiqing Zhang
    • Aihua Yu
    • Hairui Wang
    • Yang Hu
  • View Affiliations

  • Published online on: April 16, 2018     https://doi.org/10.3892/mmr.2018.8887
  • Pages: 8385-8390
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Acne rosacea is a type of chronic dermatosis with the characteristics of erubescence, angiotelectasis and pustule formation. However, current treatment methods are limited due to the side effects. Artesunate demonstrated a promising therapeutic efficacy with a high safety margin. HaCaT cells were treated with antibacterial peptide LL‑37 to simulate rosacea caused by Demodex folliculorum (D. folliculorum) infection. Cell Counting kit 8 and flow cytometry assays were performed to measure cellular proliferation, apoptosis, the stage of the cell cycle and reactive oxygen species generation in order to determine the level of cell damage. Then the damaged cells were treated with different concentrations of artesunate and doxycycline to determine the therapeutic effect of artesunate. Pro‑inflammatory cytokines tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6, IL‑8 and C‑C motif chemokine 2 (MCP‑1) were measured using an ELISA, while western blotting was used to detect the expression of Janus kinase 2 (JAK2) and signal transducer and transcription activator (STAT3). As a result, LL‑37 treated HaCaT cells decreased in cell viability, had an increased apoptotic rate and cell cycle arrest, indicating that cell damage caused by rosacea was simulated. In addition, upregulated concentrations of the pro‑inflammatory cytokines TNF‑α, IL‑6, IL‑8 and MCP‑1 were attenuated in the artesunate group in a dose‑dependent fashion, indicating the therapeutic effect of artesunate. Furthermore, higher concentrations of artesunate exhibited an improved effect compared with the doxycycline group. In addition, increased expression levels of JAK2 and STAT3 following treatment with LL‑37 suggested that rosacea caused by D. folliculorum infection may lead to inflammation through the JAK/STAT signaling pathway. In conclusion, the potential mechanism by which damage occurs in rosacea was revealed and a promising therapeutic method against rosacea was demonstrated.

Introduction

Rosacea, also known as acne rosacea, is a type of chronic dermatosis with the characteristics of erubescence, angiotelectasis and pustule formation. Rosacea can be divided into erythematotelangiectatic rosacea (ERT) and papulopustular rosacea (PPR) in the clinic (1). The cause of rosacea remains unclear; however, it may be associated with Demodex folliculorum (D. folliculorum) infections, alcoholic drinks, spicy food and exposure to sunlight (2,3). Parasitic D. folliculorum is commonly demonstrated in human hair follicles and sebaceous glands; an overgrowth of D. folliculorum may cause disease (4). The infection rate and density of D. folliculorum measured in damaged rosacea skin was demonstrated to be significantly increased compared with healthy skin through microscopic or histopathological examination (5). Increased macrophages and Langerhans cells were observed in positive specimens of D. folliculorum, indicating a hypersensitivity reaction was induced by mite-associated follicular antigens, leading to the formation of a papulopustule (6). Previous studies have demonstrated that the expression level of matrix metalloproteinase-9 (MMP-9) has a linear correlation to the density of D. folliculorum (7,8). Upregulated MMP results in the activation of epidermal serine protease, leading to the generation of the antibacterial peptide LL-37. Therefore, D. folliculorum infection is an important exacerbating factor for rosacea.

Treatment against rosacea includes systemic drugs such as metronidazole and doxycycline, as well as locally acting drugs including metronidazole and azelaic acid according to the food and drug administration (FDA) administration on rosacea. However, certain issues exist in current therapies against rosacea. External preparations may cause local inflammation due to the damaged skin barrier function of patients with rosacea (9). In addition, oral administration of antibiotics for long-term treatment may lead to body dysbacteriosis (10). Although doxycycline is used as a non-antibiotic at a dosage of 40 mg/day, gastrointestinal adverse reactions are common in the clinic. In addition, therapy against papulopustular rosacea (PPR) recommended by the FDA demonstrated a limited curative effect on the persistent and diffuse face erythema (9).

Artesunate is an innovative antimalarial drug with a low level of side effects that was developed by Chinese researchers. It was recognized by the World Health Organization and enrolled in the 11th edition of essential drug list in 2002. Artesunate was demonstrated to exhibit anti-parasitic and anti-angiogenesis activity (1113). It was reported to inhibit delayed type hypersensitivity reactions and MMP activity (14). Vascular and inflammatory reactions are the two components necessary for rosacea. Therefore, artesunate was chosen from the anti-parasitic drugs as an alternative medicine for the treatment of rosacea. Artesunate was expected to have a similar therapeutic effect and lower side effects when compared with doxycycline. Artesunate as an inexpensive drug with a high safety profile which may benefit patients with rosacea.

Materials and methods

Cell culture and damage simulation

Cultured HaCaT cells (Nanjing KeyGen Biotech Co., Ltd., Nanjing, China) were treated with LL-37 (Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai, China) at various concentrations (0, 10, 20, 40, 60, 80 and 100 µg/ml) to establish a rosacea skin lesion model. LL-37 treated HaCaT cells were measured for cell viability, reactive oxygen species (ROS) content, cell cycle stage and apoptotic rate to evaluate the rosacea-damage model.

Furthermore, artesunate was employed to treat the rosacea skin lesion model to evaluate the therapeutic effect on rosacea. Cultured HaCaT cells were digested with 0.25% trypsin (Solarbio, Beijing, China) and transferred into 6-well plates at 3×105 cells/well. Following incubation at 37°C for 24 h, the Dulbecco's modified Eagle's medium (DMEM; Hyclone; GE Healthcare Life Sciences, Logan, UT, USA) was discarded and LL-37 with a final concentration of 60 µg/ml was added into each well except for the control group, which received an equal volume of medium instead. Different concentrations (1, 10 and 50 µM) artesunate (Shanghai Aladdin Biochemical Technology Co., Ltd.) and 20 µg/ml doxycycline (Shanghai Aladdin Biochemical Technology Co., Ltd.) were added to the experimental groups. Following incubation at 37°C for 48 h, cells were digested with 0.25% trypsin, and collected for ELISA and western blotting assays.

Cell Counting kit-8 (CCK-8) assay

Cultured HaCaT cells treated with different concentrations of LL-37 (0, 10, 20, 40, 60, 80 and 100 µg/ml) were mixed with 100 µl serum-free DMEM (Hyclone; GE Healthcare Life Sciences) containing 10% CCK-8 (Dojindo Molecular Technologies, Inc., Kumamoto, Japan) and incubated in 5% CO2 at 37°C for 1 h. The optical density (OD)450 nm of the cell suspension was measured using a spectrophotometer in order to evaluate the cell viability of HaCaT cells.

Flow cytometry assay

Cultured HaCaT cells were washed using PBS and digested at 37°C with 0.25% trypsin following the treatment with LL-37 for 24 h, then centrifugation was performed at 150 × g at 4°C for 10 min. Cells were collected and resuspended with dyeing buffer containing 50 µM dihydroethidium (Wieglas Biotech (Beijing) Co., Ltd., Beijing, China). Then ROS were measured using a flow cytometer (Accuri C6; BD Biosciences, Franklin Lakes, NJ, USA) and analyzed with Accuri C6 software version 1.0.264 (BD Biosciences).

To measure apoptosis, cultured HaCaT cells were collected using 0.25% trypsin and washed with PBS, followed by the centrifugation at 150 × g at 4°C for 5 min. The supernatant was then discarded and the cells were incubated with Annexin V fluorescein isothiocyanate apoptosis detection kit (BD Biosciences) for 10 min at room temperature without light. The cellular apoptotic rate was measured and the data was obtained using a flow cytometer (Accuri C6) and Accuri C6 software version 1.0.264 (BD Biosciences).

In addition, HaCaT cells were digested with 0.25% trypsin and washed with PBS, followed by the addition of 70% pre-cooled ethanol at 4°C for 12 h and the RNA was removed using 1 µg/ml RNaseA. Then cells were stained with propidium iodide (PI) for 10 min at room temperature and the DNA content was measured using a flow cytometer (Accuri C6) and Accuri C6 software Version 1.0.264 (BD Biosciences) to determine the proportion of cells in each stage of cell cycle.

ELISA

The ELISA method was adapted to measure the content of interleukin (IL)-6 (JYM0140Hu), IL-8 (JYM0139Hu), C-C motif chemokine 2 (MCP-1, JYM0136Hu) and tumor necrosis factor-α (TNF-α, JYM0110Hu) in HaCaT cells by determining the absorbency at 450 nm. The ELISA kits were provided by Wuhan Colorful Gene Biological Technology (Wuhan, China). A total of ~100 µl culture medium was processed according to the manufacturer's protocol. The concentrations of IL-6, IL-8, MCP-1 and TNF-α were calculated according to the standard curve, which was generated from a series of different known concentrations of standard bovine serum albumin.

Western blot analysis

Cells were seeded at 3×105 cells/well in 6-well plates and duplicated wells were treated with or without (control group) 60 µg/ml LL-37 at 37°C for 48 h. Following this, cell lysates were prepared in a RIPA lysis buffer (BYL40825; JRDUN Biotech, Shanghai, China). Total protein concentration in each sample was assayed by the bicinchoninic method (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Aliquots (20 mg total protein) of each sample were then loaded on 12.5% SDS-polyacrylamide gels. Following electrophoresis, the proteins were transferred onto a nitrocellulose blotting membrane (EMD Millipore, Billerica, MA, USA), blocked with 5% nonfat milk and immunoblotted with specific antibodies overnight at 4°C. The sources of the primary antibodies were as follows: Anti-Janus kinase 2 (JAK2; cat. no. 3230; 1:1,000; CST Biological Reagents Co., Ltd., Shanghai, China), phosphorylated (p)-JAK2 (cat. no. 8082; 1:800; CST Biological Reagents Co., Ltd.), signal transducer and transcription activator (STAT3; cat. no. Ab50761; 1:100), p-STAT3 (cat. no. Ab76315; 1:2,000; both Cambridge, UK Abcam) and GAPDH (cat. no. 5174; 1:1,500; CST Biological Reagents Co., Ltd.). The membranes were then washed with TBST (0.1% Tween) buffer and incubated with horseradish peroxidase conjugated secondary antibodies (A0208 and A0216; 1:1,000; Beyotime Institute of Biotechnology, Shanghai, China) for 1 h at room temperature. The membranes were then washed with TBST (0.1% Tween) buffer and developed according to the enhanced chemiluminescence protocols (EMD Millipore). The films of western blotting were then scanned using a Bio-Rad imaging densitometer (Model GS-700) and the densities of the bands were semi-quantified using Quantity One software version 4.2.1 (Bio-Rad Laboratories, Inc., Hercules, CA, USA).

Statistical analysis

Data were expressed as the mean ± standard deviation of at least three independent replicates and analyzed using analysis of variance and Tukey's post-hoc test. GraphPad Prism 5.0 (GraphPad Software, Inc., San Diego, CA, USA) software was used to perform the analysis of data. P<0.05 was considered to indicate a statistically significant difference.

Results

LL-37 causes cell damage in a rosacea skin model

HaCaT cells treated with LL-37 were used in the CCK-8 assay to measure cell viability (Fig. 1). As illustrated in Fig. 1, the proliferation of HaCaT cells treated with 10 µg/ml LL-37 was significant at 24, 48 and 72 h (P<0.001, respectively) compared with the control (0 µg/ml), indicating that the viability of HaCaT cells was inhibited by LL-37 in a time-dependent manner. In addition, the HaCaT cells treated with various concentrations of LL-37 demonstrated a decreased proliferation rate in a dose-dependent fashion. Then flow cytometry was used to measure the levels of ROS, cell apoptosis and cell cycle progression (Fig. 2). ROS content was measured to evaluate the level of cell damage in the model. As exhibited in Fig. 2A, the fluorescence intensity of LL-37 treated cells was increased compared with the control cells, indicating a high level of ROS content in rosacea damaged cells. In addition, the induced apoptotic rate and cell cycle arrest demonstrated cell damage caused by LL-37, and indicated that the rosacea skin damage model was appropriate (Fig. 2B and C).

Artesunate attenuates cell damage caused by LL-37

The concentrations of IL-6, IL-8, MCP-1 and TNF-α were measured using an ELISA. As the results exhibit in Fig. 3, the concentrations of all the indices increased significantly in the LL-37 treated groups compared with the control, while they were attenuated by treatment with various concentrations of artesunate (1, 10 and 50 µM) in a dose-dependent manner. HaCaT cells treated with 50 µg/ml artesunate demonstrated a significantly improved therapeutic effect on LL-37 treated cells compared with the doxycycline group (P<0.001; Fig. 3).

Artesunate inhibits cell damage through the JAK-STAT3 signaling pathway

Western blotting was employed to measure the expression level of proteins associated with the JAK-STAT signaling pathway. The upregulated expression levels of p-JAK2/JAK2 and p-STAT3/STAT3 were attenuated by artesunate (1, 10 and 50 µM) dose-dependently (Fig. 4).

Discussion

Vascular and inflammatory reactions are the two required components for rosacea (15). Expansion of blood vessels and lymphatics were demonstrated in patients with rosacea according to data obtained from deformation analysis, immunohistochemistry analysis, gene microarray and reverse transcription-polymerase chain reaction; an increase in vascular endothelial growth factor, vessel marker cluster of differentiation-31 and lymphatic marker D2-40 were also observed (1619). Patients with PPR or ETR are sensitive to various stimuli including vasodilators and spicy food. The neuropeptides released from nerve endings may cause partial congestion, edema and erythema, along with the recruitment of neutrophil granulocytes and the release of mastocytes, leading to an inflammatory response. These results associated with the vascular reaction concur with the persistent face erythema and angiotelectasis exhibited in the clinic (7,20).

Innate immune response enhancement is involved in the early stages of rosacea. Previous studies demonstrated that toll-like receptor 2, antibacterial peptide LL-37, serine protease and MMP were upregulated in areas of skin damage in patients with rosacea (7,21). Furthermore, except for the increase in antibacterial peptides and kallikrein-related peptidase 5, the mRNA expression level of neutrophil chemotactic agent IL-8 rose significantly (7,21). A synergistic effect exists between the innate immune response and novel blood vessels/neural immune disorders in the angiectasis and the inflammatory cascade (22). Angiectasis contributes to the progression of the inflammatory response, while LL-37 exhibits high angiogenic activity and variety of signaling pathways which stimulate alterations in the endothelial cells (7).

The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines (23). It is involved in proliferation, differentiation, apoptosis and immunoregulation. JAK is a type of non-transmembrane form of tyrosine kinase, while STAT is called a signal transducer and transcription activator. STAT serves a critical role in signal transduction and gene transcription. The JAK-STAT signaling pathway has a wide range of functions, which are focused on the immune response and immunoregulation. Chemokines are secreted by leukocytes and stromal cells in the hematopoietic microenvironment (24). Chemokines attached to endothelial cells have a chemotactic, activatory effect on neutrophil granulocytes, mononuclear leucocytes, lymphocytes, eosinophilc granulocytes and basophilic granulocytes. IL-8 representing the a subfamily, exhibits a chemotaxis effect on neutrophilic granulocytes, while MCP-1, which represents the b subfamily, induces mononuclear leucocytes (25). IL-8, known as a neutrophil chemotactic factor, is an important factor in inflammatory disease. It serves a vital role in anti-infection, anti-cancer and immune response regulation. IL-8 is strongly chemotactic to specific and non-specific immune cells, particularly neutrophilic granulocytes, as well as lymphocytes and basophilic granulocytes. The level of inflammatory factor IL-8 increases significantly at inflammatory sites, and in serum and bodily fluids during infection or immunological disease. Therefore, the measurement of IL-8 levels was used for the diagnosis and prognosis of inflammatory diseases (26).

In the present study, cell damage in rosacea caused by D. folliculorum infection was simulated using HaCaT cells treated with LL-37 and the therapeutic effect of artesunate against rosacea was demonstrated. In addition, the results obtained from the present study revealed the injury mechanisms involved in rosacea. LL-37 treated HaCaT cells demonstrated cell damage including lower cell proliferation, increased apoptotic rate and ROS levels, and induced cell cycle arrest, indicating damage caused by LL-37 on HaCaT cells. Furthermore, the production of pro-inflammatory cytokines, including TNF-α, IL-6, IL-8 and MCP-1, in LL-37 treated HaCaT cells was increased when compared with the control group, while the levels were attenuated in the artesunate groups in a dose-dependent manner, corresponding to the expression level of JAK2 and STAT3 measured by the western blotting assay. The activation of the JAK/STAT signaling pathway upregulated the expression of pro-inflammatory cytokines including TNF-α, IL-6, IL-8 and MCP-1, which resulted in inflammation, and was attenuated by the treatment with artesunate. The deactivation of the JAK/STAT signaling pathway detected in the artesunate groups suggested that the activation of JAK/STAT signaling pathway was inhibited by artesunate, followed by the suppressed expression of pro-inflammatory cytokines TNF-α, IL-6, IL-8 and MCP-1.

In addition, it was demonstrated that the concentration of TNF-α, IL-6, IL-8 and MCP-1 in HaCaT cells treated with a high level of artesunate was lower than those in the doxycycline treated group, which was indicative of the improved therapeutic and antibacterial effect of artesunate. This result revealed a promising treatment for rosacea and provides experimental data for future clinical research.

In conclusion, the therapeutic and antimicrobial effect of artesunate on rosacea caused by D. folliculorum infection was demonstrated. The present study provided reliable data for future animal experimentation and clinical research. Artesunate may be a promising novel therapeutic method for the treatment of rosacea.

Acknowledgements

Not applicable.

Funding

The present study was supported by grants from Shanghai City Key Medical Specialties in B Construction Projects (grant no. ZK2012B18), the Special Construction Project of Weak Field of Traditional Chinese Medicine in Shanghai Municipal Health Planning Commission (grant no. BR2K2016014) and the Medical Key Subject Construction Project of Jiading District of Shanghai Municipality (grant no. ZD06).

Availability of data and materials

All data generated or analyzed during the present study are included in this published article.

Authors' contributions

TL and YH conceived and designed the study. TL, QZ, XC, GW, HZ, AY and HW performed the experiments. TL and YH wrote the manuscript. All authors read and approved the manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare they have no competing interests.

References

1 

Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R and Powell F: Standard classification of rosacea: Report of the national rosacea society expert committee on the classification and staging of rosacea. J Am Acad Dermatol. 46:584–587. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Del Rosso JQ: Management of cutaneous rosacea: Emphasis on new medical therapies. Expert Opin Pharmacother. 15:2029–2038. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Tüzün Y, Wolf R, Kutlubay Z, Karakuş O and Engin B: Rosacea and rhinophyma. Clin Dermatol. 32:35–46. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Lazaridou E, Giannopoulou C, Fotiadou C, Vakirlis E, Trigoni A and Ioannides D: The potential role of microorganisms in the development of rosacea. J Dtsch Dermatol Ges. 9:21–25. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Roihu T and Kariniemi AL: Demodex mites in acne rosacea. J Cutan Pathol. 25:550–552. 1998. View Article : Google Scholar : PubMed/NCBI

6 

Georgala S, Katoulis AC, Kylafis GD, Koumantaki-Mathioudaki E, Georgala C and Aroni K: Increased density of Demodex folliculorum and evidence of delayed hypersensitivity reaction in subjects with papulopustular rosacea. J Eur Acad Dermatol Venereol. 15:441–444. 2001. View Article : Google Scholar : PubMed/NCBI

7 

Del Rosso JQ: Advances in understanding and managing rosacea: Part 1: Connecting the dots between pathophysiological mechanisms and common clinical features of rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet Dermatol. 5:16–25. 2012.PubMed/NCBI

8 

Bonamigo RR, Bakos L, Edelweiss M and Cartell A: Could matrix metalloproteinase-9 be a link between Demodex folliculorum and rosacea? J Eur Acad Dermatol Venereol. 19:646–647. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Parodi A, Drago F, Paolino S, Cozzani E and Gallo R: Treatment of rosacea. Ann Dermatol Venereol. 138 Suppl 3:S211–S214. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Sanchez J, Somolinos AL, Almodóvar PI, Webster G, Bradshaw M and Powala C: A randomized, double-blind, placebo-controlled trial of the combined effect of doxycycline hyclate 20-mg tablets and metronidazole 0.75% topical lotion in the treatment of rosacea. J Am Acad Dermatol. 53:791–797. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Ho WE, Peh HY, Chan TK and Wong WF: Artemisinins: Pharmacological actions beyond anti-malarial. Pharmacol Ther. 142:126–139. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Van Agtmael MA, Eggelte TA and van Boxtel CJ: Artemisinin drugs in the treatment of malaria: From medicinal herb to registered medication. Trends Pharmacol Sci. 20:199–205. 1999. View Article : Google Scholar : PubMed/NCBI

13 

der Meersch Van H: Review of the use of artemisinin and its derivatives in the treatment of malaria. J Pharm Belg. 60:23–29. 2005.(Article in French). PubMed/NCBI

14 

Rasheed SA, Efferth T, Asangani IA and Allgayer H: First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer. 127:1475–1485. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Cribier B: Pathophysiology of rosacea: Redness, telangiectasia, and rosacea. Ann Dermatol Venereol. 138 Suppl 3:S184–S191. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Gomaa AH, Yaar M, Eyada MM and Bhawan J: Lymphangiogenesis and angiogenesis in non-phymatous rosacea. J Cutan Pathol. 34:748–753. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Yamasaki K and Gallo RL: The molecular pathology of rosacea. J Dermatol Sci. 55:77–81. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Steinhoff M, Buddenkotte J, Aubert J, Sulk M, Novak P, Schwab VD, Mess C, Cevikbas F, Rivier M, Carlavan I, et al: Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 15:2–11. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Rosina P, Zamperetti MR, Giovannini A, Chieregato C and Girolomoni G: Videocapillaroscopic alterations in erythematotelangiectatic rosacea. J Am Acad Dermatol. 54:100–104. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Drummond PD and Su D: Blushing in rosacea sufferers. J Psychosom Res. 72:153–158. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Yamasaki K, Di Nardo A, Bardan A, Murakami M, Ohtake T, Coda A, Dorschner RA, Bonnart C, Descargues P, Hovnanian A, et al: Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 13:975–980. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Del Rosso JQ: Advances in understanding and managing rosacea: Part 2: The central role, evaluation, and medical management of diffuse and persistent facial erythema of rosacea. J Clin Aesthet Dermatol. 5:26–36. 2012.PubMed/NCBI

23 

Bernardino L, Xapelli S, Silva AP, Jakobsen B, Poulsen FR, Oliveira CR, Vezzani A, Malva JO and Zimmer J: Modulator effects of interleukin-1beta and tumor necrosis factor-alpha on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures. J Neurosci. 25:6734–6744. 2005. View Article : Google Scholar : PubMed/NCBI

24 

Oberbach A, Schlichting N, Blüher M, Kovacs P, Till H, Stolzenburg JU and Neuhaus J: Palmitate induced IL-6 and MCP-1 expression in human bladder smooth muscle cells provides a link between diabetes and urinary tract infections. PLoS One. 5:e108822010. View Article : Google Scholar : PubMed/NCBI

25 

Deshmane SL, Kremlev S, Amini S and Sawaya BE: Monocyte chemoattractant protein-1 (MCP-1): An overview. J Interferon Cytokine Res. 29:313–326. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Bailey C, Negus R, Morris A, Ziprin P, Goldin R, Allavena P, Peck D and Darzi A: Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis. 24:121–130. 2007. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June-2018
Volume 17 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Li T, Zeng Q, Chen X, Wang G, Zhang H, Yu A, Wang H and Hu Y: The therapeutic effect of artesunate on rosacea through the inhibition of the JAK/STAT signaling pathway Retraction in /10.3892/mmr.2023.13127. Mol Med Rep 17: 8385-8390, 2018
APA
Li, T., Zeng, Q., Chen, X., Wang, G., Zhang, H., Yu, A. ... Hu, Y. (2018). The therapeutic effect of artesunate on rosacea through the inhibition of the JAK/STAT signaling pathway Retraction in /10.3892/mmr.2023.13127. Molecular Medicine Reports, 17, 8385-8390. https://doi.org/10.3892/mmr.2018.8887
MLA
Li, T., Zeng, Q., Chen, X., Wang, G., Zhang, H., Yu, A., Wang, H., Hu, Y."The therapeutic effect of artesunate on rosacea through the inhibition of the JAK/STAT signaling pathway Retraction in /10.3892/mmr.2023.13127". Molecular Medicine Reports 17.6 (2018): 8385-8390.
Chicago
Li, T., Zeng, Q., Chen, X., Wang, G., Zhang, H., Yu, A., Wang, H., Hu, Y."The therapeutic effect of artesunate on rosacea through the inhibition of the JAK/STAT signaling pathway Retraction in /10.3892/mmr.2023.13127". Molecular Medicine Reports 17, no. 6 (2018): 8385-8390. https://doi.org/10.3892/mmr.2018.8887